The trypanocide Suramin was tested as a possible antagonist at the P2‐purinoceptor of the mouse vas deferens. At a concentration of 100 μm, Suramin antagonized the response to α,β‐methylene ATP, while responses to carbachol and noradrenaline were unaffected. These results suggest that Suramin may provide a starting point for the development of specific antagonists for P2‐purinoceptors.
SUMMARY1. Excitatory junction potentials (e.j.p.s) were recorded intracellularly in the guinea-pig vas deferens following stimulation ofthe hypogastric nerve. Differentiation of the rising phase of the e.j.p. showed them to be made up of transient peaks in the rate of depolarisation, the 'discrete events'.2. In any one cell discrete events occurred at one or several latencies, intermittently, the frequency of occurrence varying between 1 in 1*8 to 1 in 45 stimuli.3. Intermittence was not an artifact due to the use of submaximal stimulation nor the result of a ganglionic relay between the hypogastric and vas deferens nerve.4. Discrete events occurring with a single latency had amplitudes that were multimodally distributed. In some cells the preferred values of amplitude were simple whole number multiples of the smallest preferred value.5. The time course of discrete events varied from cell to cell and at different latencies. The discrete event had a time to peak of 5-3 + 1 9 msec, n = 220 (mean + S.D.) and a time to half decay of 8*3 + 3-6 msec, n = 220.6. Discrete events in a cell could be matched for amplitude and time course by spontaneous excitatory junction potentials in the same cell and both probably represent the release of a single packet of transmitter.7. The e.j.p. is made up of (1) discrete events which represent the release of transmitter from a single varicosity, (2) a non intermittent slow component which represents the electronic spread of activity from smooth muscle excited from distant release sites.8. It is concluded that transmitter release from individual varicosities is packeted and the number of packets liberated per stimulus from a single varicosity is small, varying between zero and 10.
(1960) and by Brandon & Rand (1961). These authors used the contractile response of the effector organ as an index ofthe amount of transmitter liberated. Interpretation of their results is, however, difficult because not only are we ignorant of the relation between transmitter liberation and effector response, but, as Vane (1962) has pointed out, many drugs alter non-specifically the tissue response to catechol amines. We have therefore done our experiment by collecting venous blood from the spleen of the cat and estimating the noradrenaline liberated by stimulation of the nerves.Cocaine, anticholinesterases and hexamethonium do not appear to affect the liberation of noradrenaline by the nerves or its uptake by the tissues of the spleen. METHODSCats were anaesthetized with ethyl chloride, ether and intravenous chloralose 80 mg/kg. The spleen, its nerve supply, arteries and venous drainage were prepared as described by Brown & Gillespie (1957), except that instead of tying the splenic nerve early in the preparation, we left ligation as late as possible in order to prevent those effects of neuronal rest that may appear after 1-2 hr (Brown, Davies & Ferry, 1961). In some experiments the spleen was perfused with the cat's own blood through a constant-output perfusion pump. This consisted of a tube of silicone rubber compressed by three plates. The two outer plates were input and output valves, the larger, middle or ventricular plate compressed most of the tubing between the valves. The valves and ventricles were operated by pulses of air produced in three coupled compressors which ran at 90 c/min. The output of the pump could be varied by altering the stroke volume. In most experiments the stomach and duodenum were removed in order to gain better access to the arterial supply of the spleen. Blood was taken from the cat through a polythene cannula placed in the stump of the superior mesenteric artery and, after passing through the pump, was ejected into the coeliac axis through a cannula placed in the hepatic artery. The coeliac axis was tied between the aorta and the hepatic artery after the pump hadbeenconnected and had begun to pump blood into the coeliac axis; there was thus no interruption of the blood supply to the spleen. Experiments showed that, if the splenic blood supply was interrupted, the resistance to * M.R.C. Scholar.
The competitive α‐ and β‐adrenoceptor blocking agent labetalol, in concentrations up to 10−4 M, produced dose‐dependent increases in transmitter overflow from the isolated blood perfused spleen of the cat following nerve stimulation at 10 and 30 Hz. At concentrations above 10−4 M labetalol produced a pronounced decrease in transmitter overflow. Labetalol (1.5 × 10−4M) increased the recovery of 3H label in the venous blood following the close‐arterial infusion of [3H]‐(‐)‐noradrenaline indicating that the drug inhibits uptake of the amine. Both labetalol (3.8 × 10−5 M) and piperoxan (7.4 × 10−6 M) produced parallel shifts to the right of the dose‐response curves to noradrenaline and oxymetazoline in isolated strips of cat splenic capsule. In this preparation both drugs acted as competitive postsynaptic α‐adrenoceptor blocking agents. Labetalol (3.3 × 10−5M) increased the transmitter overflow following stimulation of the splenic nerves with 200 impulses at 10 Hz. The overflow could be further increased by subsequent addition of piperoxan (7.2 × 10−6M). Piperoxan (5.7 × 10−6M) alone produced a marked increase in transmitter overflow which could be further increased by subsequent addition of desmethylimipramine (DMI; 3.2 × 10−5M). Cocaine (1.5 × 10−5M) or DMI (5.4 × 10−5M) produced a small increase in transmitter overflow which was not further increased by addition of labetalol (2.8 × 10−5 M). Labetalol produced a biphasic effect on the responses of the isolated blood perfused spleen of the cat to nerve stimulation. With low doses (up to 10−4M) vascular responses were potentiated and with high doses (greater than 10−4M) inhibited. The potentiation was related to uptake blockade and the inhibition to decreased transmitter overflow and postsynaptic α‐adrenoceptor blockade. Labetalol appears to act as a postsynaptic α‐adrenoceptor antagonist in the isolated blood perfused spleen of the cat with little effect on presynaptic α‐adrenoceptors. The moderate elevation of transmitter overflow by the drug is related to the inhibitory effect of the drug on neuronal uptake rather than on presynaptic α‐adrenoceptors.
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